Developing cell-based therapies for pancreatic ductal adenocarcinoma
Rachel Elizabeth Ann Fincham, … , Joe Poh Sheng Yeong, Hemant Mahendrakumar Kocher
Rachel Elizabeth Ann Fincham, … , Joe Poh Sheng Yeong, Hemant Mahendrakumar Kocher
Published April 15, 2025
Citation Information: J Clin Invest. 2025;135(8):e189513. https://doi.org/10.1172/JCI189513.
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Commentary

Developing cell-based therapies for pancreatic ductal adenocarcinoma

Abstract

Prostate stem cell antigen (PSCA) is highly and preferentially expressed on the surface of pancreatic ductal adenocarcinoma (PDAC) cells, raising the promise of tumor-selective cell-based immunotherapies. In this issue of the JCI, Dai et al. harness PSCA for the development of an off-the-shelf chimeric antigen receptor (CAR) invariant natural killer T (iNKT) cell–based treatment for PDAC. Through in vitro experiments and in vivo models, the authors demonstrate selectivity and therapeutic efficacy of PSCA CAR_sIL15 iNKT cells against both gemcitabine-sensitive and -resistant PDAC cells with comparable antitumor activity for freshly produced and frozen off-the-shelf PSCA CAR_sIL15 iNKT cells. This development opens another potential therapeutic option for pancreatic cancer.

Authors

Rachel Elizabeth Ann Fincham, Joe Poh Sheng Yeong, Hemant Mahendrakumar Kocher

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Figure 1

CAR-invariant NKT cells engage via the CD1d receptor on malignant and antigen-presenting cells.

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CAR-invariant NKT cells engage via the CD1d receptor on malignant and an...
CAR-invariant NKT cells target malignant cells through engagement of their CAR with the target antigen present on the cancer cell surface. Binding induces rapid cytokine release, stimulating recruitment of additional immune cell subsets, such as T cells and NK cells. In addition, CAR-iNKT cells induce direct tumor cell cytolysis through perforin release. CAR-iNKT cells may also engage with malignant cells through invariant NKT TCR engagement with tumor antigens presented via the CD1d receptor. While some tumoral cells express CD1d, this receptor-ligand interaction is largely mediated by antigen-presenting cells. Signaling through CD1d does not involve engagement of the MHCs and thus prevents induction of GvHD, a common adverse event observed in response to allogeneic CAR-T cell treatment.